Method for determining the adequacy of dialysis

ABSTRACT

A method for determining the adequacy of dialysis, using determination of urea concentration in the dialysate effluent with an enzymatic urease sensor, and conversion of this information to arterial urea nitrogen utilizing a flow ratio correction; and utilizing the arterial blood urea nitrogen derived from readings of an on-line monitoring sensor as an absolute quantity, and the urea reduction ratio as a relative quantity as a new end-point for dialysis adequacy.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a method of monitoring dialysis patients toensure that there is adequate dialysis.

2. Description of the Related Art

Dosimetry of dialytic treatment of end-stage renal disease (ESRD) istraditionally specified in terms of time or duration of dialysis. Likethe elevation of blood pressure in hypertension or the elevation ofsugar in diabetes, ESRD manifests itself with elevation of retentionproducts. Although there is no ideal marker to represent uremic toxins,urea is the best marker, and currently the goal of dialysis is primarilyaimed at clearance of urea. Urea level is subject not only to urearemoval by dialysis in ESRD, but also to urea generation by proteincatabolism and the level of protein intake. A high blood urea nitrogen(BUN) is generally accompanied by increased morbidity. Middle-sizedmolecules such as vitamin B₁₂ and larger molecules like parathormone(PTH) and β₂ microglobulins have yielded poor correlations with adequatedialysis. Thus, dialysis therapy is geared toward the reduction of ureaand other uremic toxins so that their concentrations approach almostnormal level.

Use of the index of time or duration of dialysis is the current methodused to determine the adequacy of dialysis. This method rather thanprescribing a particular dosage of treatment can present problems forpatients whose reaction to dialysis does not follow the predictedpattern. Recent studies have pointed to the use of time as an end-pointin dialysis therapy as a main factor in the high mortality rates fordialysis in the United States, where the average treatment time is lessthan 12 hours per week, as compared with Japan and Europe where theaverage weekly treatment times are 15 and 12 hours per week,respectively. See Brunner et al., Am. J. Kidney Dis. 15:384-396, 1990.

The current methods for calculating dialysis prescription and forassuring the adequacy of dialysis treatment include such indices as KT/V(with K=dialyzer clearance, T=time of dialysis and V=volume ofdistribution of urea, which may change due to ultrafiltration); the timeaverage concentration of blood urea (TAC_(urea)), the protein catabolicrate (PCR) and the urea reduction ratio (URR). These have recently beenreviewed by Hakim et al., Am. J. Kidney Dis. 20:107-124, 1992. KT/V hasbeen calculated in the past from the equation: KT/V=-ln(C_(t) /C_(o)-0.008t-UF/W where C_(t) is the postdialysis urea level and C_(o) is thepredialysis urea level; t is the time; UF is the ultrafiltrate removed;and W is the postdialysis weight (Daugirdas, JT, Int. J. Artif. Organs12:420-427, 1988). TACurea represents an average urea concentration, andreflects exposure to the uremic toxin urea, which should generally bebelow 50 mg/dl for a low morbidity. The indices TAC_(urea) and PCR,while serving as relevant indicators of adequacy of dialysis, cannot beused to prescribe dialysis. The methods used for defining the dialysisprescription time dose are all based on indices derived from ureastudies, which involve arguably questionable assumptions and estimates,and are indirect techniques.

It is therefore an object of this invention to provide a reliable methodfor defining the end-point of dialysis to insure the adequacy ofdialysis.

It is a further object of this invention to provide a non-invasive,accurate method of determining whether dialysis has to proceed for asufficient time, utilizing measurements of urea concentration in theeffluent dialysate.

Other objects and advantages will be more fully apparent from thefollowing disclosure and appended claims.

SUMMARY OF THE INVENTION

The invention is a method for determining the adequacy of dialysis,comprising determination of urea concentration in the dialysate effluentwith an enzymatic urease sensor. This information is converted toarterial urea nitrogen utilizing a flow ratio correction. Arterial ureanitrogen derived from readings of an on-line monitoring sensor may beutilized as an absolute quantity, or may be used to determine therelative urea reduction ratio, as an end-point for dialysis adequacy.

Other aspects and features of the invention will be more fully apparentfrom the following disclosure and appended claims.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS THEREOF

The present invention provides a method comprising utilizingelectrometric measurements of urea concentration in effluent dialysateto calculate arterial blood urea nitrogen (BUN) using equationsdiscussed below. Arterial BUN is a reliable index of the dialysisprocess if the protein catabolic rate is constant and adequate proteinintake of 0.8-1.4 g/day is maintained in the steady-state.

In particular, the method of the invention for determining the adequacyof dialysis of a patient, comprises:

(a) providing an enzymatic urease-based sensor;

(b) using said sensor to determine the concentration of urea indialysate from said dialysis;

(c) determining rates of venous blood flow, dialysis fluid flow andarterial blood flow;

(d) determining a flow ratio defined as the sum of said rates of venousblood flow and said dialysis fluid flow, divided by the rate of arterialblood flow;

(e) determining urea nitrogen concentration in the blood of said patientutilizing said urea concentration in dialysate and said flow ratio; and

(f) ceasing dialysis of said patient when said urea nitrogenconcentration in the blood reaches a predetermined level.

The preferred method further comprises making multiple on-linemeasurements of the concentration of urea in said dialysate; andproviding a profile of urea reduction utilizing said measurements toassess the adequacy of dialysis on an ongoing basis.

Arterial blood urea nitrogen (B_(A)) is calculated using firstprinciples of urea mass balance (urea entering dialyzer=urea leavingdialyzer) and dialysate urea concentration measurements (D_(U)). Ureamass balance may be expressed as follows:

    Q.sub.A =Q.sub.D +Q.sub.D

where Q=quantity per unit time; A=arterial; V=venous; and D =dialysateeffluent.

Each of the terms of this equation is equivalent to the relevant flowrate multiplied by the relevant concentration as follows:

    BF.sub.A ×B.sub.A =(BF.sub.v ×B.sub.v)+(V.sub.D ×D.sub.U) (equation 1)

where BFA=arterial blood flow rate in ml/min; B_(A) =concentration ofurea in arterial blood reported in urea nitrogen (mg/ml); BF_(v) =venousblood flow rate (ml/min); B_(v) =concentration of urea in venous blood(mg/ml); V_(D) =flow rate of dialysis fluid (ml/min) and D_(U)=concentration of urea in dialysate (mg/ml).

Separate actual determinations of B_(V) and D_(U) show that these twonumbers are equal due to the presence of a diffusion equilibrium acrossthe dialyzer. This means that the following equation can be written:

B_(A) =D_(U) (BF_(V) +V_(D))/BF_(A) (equation 2)

All of the terms of the "flow ratio", defined as (BF_(V) +V_(D))BF_(A)can be set or adjusted and Du can be measured with a urease enzyme-basedsensor electrode as discussed above. Thus, B_(A) can be determined atfrequent time intervals.

Under the usual conditions for dialysis, BF_(V) =240 ml/min; BF_(A) =250ml/min and V_(D) =510 ml/min. In comparison, the ultrafiltration(removal of fluid from the blood to the dialysate during dialysis) isfinite and relatively small. Thus, in the standard case, ultrafiltrationmay be adjusted to, for example, 2.41 (about 5.31 lb) over a period of 4hours of dialysis. This is equivalent to 2400 ml/240 minutes or 10ml/minute.

In the preferred embodiment of the invention a urea sensor isincorporated into the artificial kidney to continuously monitor arterialBUN in the dialysate. Such an element incorporates a urease enzymesensor located in the dialysate effluent stream, and as such, is distalto the extracorporeal stream so that it does not contaminate the returnblood flow to the patient. An ideal location for the urea sensor wouldbe at the arterial outflow, but the urease is poisoned by the presenceof blood. By using the volume flow ratio, the arterial blood urea can bereliably calculated. Thus, depending on how often the readings aretaken, on-line and/or continuous calculations of arterial BUN may bedone. With use of technology known in the art, on-line measurements ofthe concentration of urea in the dialysate (D_(U)) can be obtained, thusproviding a profile of urea reduction that can be used to assess theadequacy of dialysis. A simple example of an on-line sampling portcomprises a three-way connector to allow frequent sampling. Sincesampling is from outgoing dialysate (towards the drain), contaminationis not a risk factor.

In another embodiment of the invention, the arterial BUN calculationsare used along with time of dialysis and other selected dialysis indicesknown in the art such as PCR and TAC_(urea) to provide a more accuratemeasure of the adequacy of dialysis. Parameters such as KT/V and URR canbe manipulated to adjust dialysis dosimetry. The KT/V of the delivereddialysis session may be determined by knowing the predialysis andpostdialysis BUN. Thus, KT/V, which can be calculated by multiplying thedialyzer clearance (K) as supplied by the manufacturer, which is flowdependent, by the time of dialysis, and dividing by the volume ofdistribution of urea, may be predicted by the arterial BUN readingsobtained according to the invention. This allows adjustment of theindividual time of dialysis or trouble-shooting of problems such asinadequate effective blood flow (even at best, the arterial blood flowis gradually built up at the beginning of dialysis), dialysate flowproblems, or calculations of time (interruptions due to pressurebuilding up and the like) that may significantly reduce the amount ofdelivered dialysis.

Readings of BUN obtained according to the invention as derived simplyfrom direct measurements can also be used to calculate URR which alsoadds another parameter to assessing the adequacy of dialysis. Whereasthe individual BUN readings provide an absolute measurement and a targetvalue, for example, <30 mg/dl, to end the dialysis session, URR providesa relative measure. This is useful in some cases where initial plasmaurea concentration is relatively low, such as with low protein intake,and therefore, the individual dialysis session may be ad]usted toaccomplish a URR, for example, of about 65% of the target value toinsure adequate dialysis.

The invention herein thus preferably includes three main components: (1)monitoring urea in dialysate effluent using an enzymatic urease sensor;(2) converting the dialysate urea nitrogen (DUN) to the simultaneousarterial urea nitrogen (BUN) by multiplying the flow ratio correctiontimes the DUN; and (3) utilizing the BUN derived from readings of anon-line monitoring sensor directly (arterial BUN}as an absolute quantityand the urea reduction ratio as a relative quantity, which is a newend-point defining the adequacy of dialysis and to estimate or determineother dialysis parameters as discussed above.

The features and advantages of the present invention will be moreclearly understood by reference to the following examples, which are notto be construed as limiting the invention.

EXAMPLES EXAMPLE I Patients emoloved in dialvsis studv

Four male patients, aged 35-59 years, with chronic renal failure whowere on maintenance dialysis were selected. No special dietaryrestrictions were employed. Patients weighed 194-260 pounds. Theirsymptoms included chronic glomerulonephritis and primary hypertension,with diabetes mellitus in one case. The patients were dialyzed for fourhours, three times a week, using a hollow fiber cellulose membrane on aBaxter SPS 550 (Terumo Company, NJ) dialysis machine.

Three experimental protocols (discussed below in more detail) wereemployed with the four patients. In all protocols used to studydialysis, ultrafiltration was constant and finite at 10 ml/min. Underall protocols, D_(U) was measured at regular intervals in dialysatesampled frequently, at which time blood samples were also obtained.Values of D_(u) were used in equation 2 above to calculate B_(A) underthe varying conditions and were also compared to B_(A) values obtainedfrom the corresponding plasma samples. Comparisons between treatmentswere performed with paired Student's t-test. A statistical significancewas determined at a two-tailed p value of <0.05.

EXAMPLE II Analysis of urea concentration

A modified NOVA 12 chemistry analyzer (Nova Biomedical, Waltham, MA),with a urease enzyme-based sensor electrode was used to measure the ureaconcentration electrometrically in aliquots of sampled dialysate atselected time intervals. Plasma and dialysate determinations of ureaconcentration using a spectrophotometric method (Abbo&t SpectrumAnalyzer, Irving, TX), were also obtained from laboratory measurementson samples obtained at the same time as the samples analyzedelectrometrically with the sensor. The laboratory measurements of bloodand dialysate urea concentrations were used as controls to validate thecalculations obtained from electrometric measurements of the dialysateurea concentrations.

EXAMPLE III First orotocol of study

In the first protocol, the patients underwent regular dialysis with theparameters on standard conditions (BF_(A) =250 ml/min and V_(D) =500ml/min). All patients were started on dialysis as usual. Within thefirst minute, a sample of arterial blood was drawn for laboratorydetermination of initial arterial BUN at time zero. Although a supple ofdialysate was also obtained at this time, it was discarded because of alack of sample equilibration within this short period of time. After onehour a second sample and two dialysate samples were obtained. The bloodsample and one of the dialysate samples were sent to the laboratory forurea concentration determinations using the spectrophotometric methoddiscussed in Example II. Urea concentration from the remaining dialysatesample at each time period was read directly using the urease-basedelectrode. The same procedure was repeated every hour until the end ofthe dialysis session for a total of five samplings per patient.

The results are shown in Table 1. The differences between the calculatedarterial BUN and the measured arterial BUN are not statisticallysignificant at any time using the paired t-test.

                  TABLE 1                                                         ______________________________________                                                       DUN.sup.1                                                                              Arterial BUN                                                                             Arterial BUN                               Subject                                                                              Time    mg %     mg % calculated.sup.2                                                                    mg % measured                              ______________________________________                                        1      0       --       --         63                                                1       14.2     42.6       46                                                2       11.8     35.4       41                                                3       10.3     30.9       31                                                4        9.2     27.6       28                                         2      0       --       --         68                                                1       16.9     50.7       50                                                2       13.8     41.4       42                                                3       11.5     34.5       34                                                4       10.0     30.0       30                                         3      0       --       --         82                                                1       20.2     60.6       57                                                2       14.4     43.2       43                                                3       12.1     36.3       35                                                4       10.0     30.0       29                                         4      0       --       --         63                                                1       15.3     45.9       49                                                2       11.8     35.4       42                                                3       11.0     33.0       36                                                4        9.3     27.9       28                                         ______________________________________                                         .sup.1 Dialysate urea nitrogen measured electrometrically.                    .sup.2 A flow ratio of 3 was used (flow ratio = (BF.sub.V +                   V.sub.D)/BF.sub.A = (240 + 510)/250 = 3).                                

EXAMPLE IV Second protocol

In the second protocol, the patients were started with an initial BF_(A)of 150 ml/min. which was then gradually increased by an increment of 50ml/min every thirty minutes to a maximum of 350 ml/min. V_(D) was keptconstant at 500 ml/min. Manipulation of the arterial flow; rate isclinically useful in order to reduce the initial urea reduction rate,and to prevent adverse reactions to fast reductions of systemic ureaconcentration which are not usually matched by concomitant decreases inurea concentration in the cerebrospinal fluid. This protocol allowedchecking of whether reliable values of arterial BUN may be obtained fromdialysate measurements of urea concentrations even when arterial flowrates are changed.

The results are shown in Table 2. The differences between the calculatedarterial BUN (from dialysate) and the measured arterial BUN (in plasma)are not statistically significant in any subject at any sampling timeusing the paired t-test.

                  TABLE 2                                                         ______________________________________                                        Sub-        BF.sub.A                                                                              FR.sup.2                                                                            DUN.sup.1                                                                           Art. BUN                                                                              Art. BUN                              ject Time   ml/min  mg %  mg %  mg % calc.                                                                            mg % meas.                            ______________________________________                                        1    0      initial --    --    --      --                                         1.0    150     4.33  12.8  54.6    48                                         1.5    200     3.50  13.5  47.3    45                                          2.25  250     3.00  13.5  40.5    39                                         3.1    300     2.67  12.7  33.9    34                                          3.75  350     2.43  10.9  26.9    27                                    2    0      initial --    --    --      --                                         1.0    150     4.33  15.6  67.5    57                                         1.5    200     3.50  15.8  55.3    55                                          2.33  250     3.00  15.6  47 0    46                                         3.2    300     2.67  14.8  39.5    40                                          3.83  350     2.43  12.6  30.6    34                                    3    0      initial --    --    --      --                                         1.0    150     4.33  16.5  71.4    54                                          1.45  200     3.50  15.0  52.4    47                                          2.15  250     3.00  14.3  42.9    42                                         3.0    300     2.67  13.5  36.1    32                                          3.67  350     2.43  12.6  30.6    25                                    4    0      initial --    --    --      --                                         1.0    150     4.33  13.0  56.3    50                                         1.5    200     3.50  14.0  49.0    47                                          2.25  250     3.00  14.1  42.3    42                                         3.1    300     2.67  13.2  35.2    36                                          3.75  350     2.43  11.7  28.4    31                                    ______________________________________                                         .sup.1 Dialysate urea nitrogen measured electrometrically.                    .sup.2 Flow ratio                                                        

EXAMPLE V Third protocol

In the third protocol, BF_(A) was kept constant at 250 ml/min whileV_(D) was increased from 300 ml/min for the first period (95 min) to 475ml/min for the second period (80 min) and finally to 650 ml/min for thelast period (65 min). Samples were taken just before changing V_(D).This protocol is another manifestation of controlling the decrease inblood urea by controlling the flow rate of the sink (in this case, thedialysate flow rate) in the hemodialysis session. Arterial BUN was againmeasured in plasma and compared to values of BUN calculated fromelectronic measurements.

Table 3 shows a summary of the results. The differences between thecalculated arterial BUN and the measured arterial BUN are notstatistically significant at any time using the paired t-test.

                  TABLE 3                                                         ______________________________________                                        Sub-        VD      FR.sup.2                                                                            DUN.sup.1                                                                           Art. BUN                                                                              Art. BUN                              ject Time   ml/min  mg %  mg %  mg % calc.                                                                            mg % meas.                            ______________________________________                                        1    0      --      --    --    --      --                                         1.33   300     2.2   15.7  34.5    34                                         2.66   475     2.9    9.2  26.7    27                                         3.66   650     3.6    6.7  24.1    24                                    2    0      --      --    --    --      --                                         1.33   300     2.2   19.7  43.3    42                                         2.66   475     2.9   11.2  32.5    33                                         3.66   650     3.6    7.7  27.7    29                                    3    0      --      --    --    --      --                                         1.33   300     2.2   19.7  43.3    38                                         2.58   475     2.9   10.9  31.6    28                                         3.58   650     3.6    6.3  22.7    22                                    4    0      --      --    --    --      --                                         1.33   300     2.2   19.2  42.2    41                                         2.58   475     2.9   11.3  32.8    34                                         3.58   650     3.6    6.9  24.8    28                                    ______________________________________                                         .sup.1 Dialysate urea nitrogen measured electrometrically.                    .sup.2 Flow ratio                                                        

While the invention has been described with reference to specificembodiments thereof, it will be appreciated that numerous variations,modifications, and embodiments are possible, and accordingly, all suchvariations, modifications, and embodiments are to be regarded as beingwithin the spirit and scope of the invention.

What is claimed is:
 1. A method of determining adequacy of dialysis of apatient, comprising:(a) providing an enzymatic urease-based sensor; (b)using said sensor to determine the concentration of urea in dialysatefrom said dialysis; (c) determining rates of venous blood flow, dialysisfluid flow and arterial blood flow in said dialysis; (d) determining aflow ratio defined as the sum of said rates of venous blood flow andsaid dialysis fluid flow, divided by the rate of arterial blood flow;(e) determining urea nitrogen concentration in the arterial blood ofsaid patient utilizing said urea concentration in said dialysate andsaid flow ratio; (f) calculating a urea reduction ratio; (g) utilizingthe arterial blood urea nitrogen concentration as an absolute quantityand the urea reduction ratio as a relative quantity to determinedialysis adequacy; and (h) ceasing dialysis of said patient when saiddialysis is adequate as determined in step (g).
 2. The method of claim1, wherein said method further cmprises making multiple measurements ofthe concentration of urea in said dialysate and calculating the arterialblood urea nitrogen and the urea reduction ratios on an ongoing basis toassess the adequacy of dialysis on an ongoing basis.